This project will use a genetically engineered mouse model of cancer to study the efficacy of drugs that inhibit the function of receptor tyrosine kinases expressed in endothelial or peri-endothelial support cells of the angiogenic vasculature that is induced during tumorigenesis. The model involves pancreatic islet carcinogenesis in RIP1-Tag2 transgenic mice, wherein a pathway unfolds through the sequential appearance of distinguishable premalignant and malignant stages. The RIP-Tag model has been used to develop a set of therapeutic trial designs that are initiated at different stages of islet carcinogenesis; the result is that certain angiogenesis inhibitors show stage-specific efficacy, with some most effective at early stages and others at late stages of disease progression. Provocatively, trials with two kinase inhibitors suggest the hypothesis that both tumor endothelial cells and tumor pericytes can be separately targeted, and that by functionally inhibiting receptor kinases on each cell type, combinatorial efficacy with broader stage specificity can be achieved. Based on exciting preliminary results, this project will test the proposition that combinatorial targeting of kinases expressed in these vascular cell types, with and without chemotherapy, can produce objective and significant responses against both premalignant (prevention) and malignant disease. The aims are to: 1. Evaluate stage specificity and relative benefits of agents that variously interfere with VEGF receptor signaling in tumor endothelial cells. 2. Investigate the hypothesis that inhibitors of PDGF receptor signaling target pericytes and thereby disrupt the tumor vasculature, impairing angiogenesis, vascular integrity, and tumor growth. 3. Evaluate combinatorial strategies involving targeting of multiple cell types with receptor tyrosine kinase inhibitors to broaden stage specificity and improve efficacy. 4. Assess efficacy and target cell types of 'metronomic' chemotherapy in the stages of islet carcinogenesis, and determine the benefits of combining traditional vs. metronomic chemotherapy with RTK inhibitors. 5. Identify biological response markers of the distinctive targeting strategies using microarray expression profiling technology that might be used in translational studies with these drugs in other models and in human clinical trials. The results will give new perspective into the potential of targeting two component cell types of the tumor vasculature with kinase inhibitors so as to broaden activity and improve efficacy in distinct stages of progression, and thereby may significantly impact the clinical applications of such agents in treating different stages and kinds of human cancer.